Polymorphisms within glutathione S-transferase genes in pediatric non-Hodgkin's lymphoma

BACKGROUND AND OBJECTIVES: Glutathione S-transferases (GSTs) are involved in the metabolism of a number of cancer chemotherapeutic agents. Certain members within the GST superfamily exhibit phenotypically relevant genetic polymorphisms which have been associated with outcome in hematologic malignant disease. DESIGN AND METHODS: In the present study we genotyped a cohort of 169 pediatric non-Hodgkin's lymphoma (NHL) patients with available specimens from the NHL-BFM trials 86 and 90 conducted by the Berlin-Frankfurt-Münster (BFM) study group to assess a potential association of phenotypically relevant glutathione S-transferase polymorphisms (GSTM1, GSTT1, GSTP1 codon 105) with treatment outcome in this patient group. RESULTS: Treatment failure in patients with mature B-cell NHL was significantly less likely to occur in patients carrying at least one GSTM1 allele in comparison to those with a homozygous deletion of GSTM1. This protective effect mediated by the presence of GSTM1 was even more pronounced within the subset of therapy group B patients at highest clinical risk of treatment failure (B-ALL, disease stage IV, disease stage III with unresected abdominal tumor, and LDH activity > or = 500 U/L). Of all events in therapy group B, 87.5% occurred in this high risk group. Within this subset, the multivariate relative risk reached 4.98 (95% CI = 1.27-19.52; p= 0.021). INTERPRETATION AND CONCLUSIONS: Our results suggest that genetic variation at the GSTM1 locus may be of clinical importance in pediatric NHL and may be a potential candidate for indicating future treatment stratification strategies.     

Mechanism of action of PD-1 receptor/ligand targeted cancer immunotherapy

Immunotherapy targeting the Programmed Death (PD-1) receptor/ligand (L) “checkpoint” rapidly gains ground in the treatment of many cancer types. To increase treatment scope and efficacy, predictive biomarkers and rational selection of co-treatments are required. To meet these demands, we must understand PD-1 function in detail. We here outline recent insights into the regulation of the CD8⁺ T cell response by PD-1. The prevailing view has been that blockade of PD-1/ligand (L) interaction “reinvigorates” cytotoxic T lymphocytes (CTL) that were rendered dysfunctional in the tumor microenvironment (TME). However, this review stresses that tumors continuously communicate with adjacent draining lymph nodes (LNs) and that the PD-1 checkpoint also operates during T cell priming. We clarify the role of the PD-(L)1 system at the T cell/DC interface, where it regulates T cell receptor (TCR) signaling and CD28 costimulation and thus controls activation of tumor-specific T cells. We also highlight the importance of CD4⁺ T cell help during priming, which allows DCs to provide other costimulatory and cytokine signals required for optimal CTL differentiation and likely avoidance of a dysfunctional state. Therefore, we pose that PD-(L)1 blockade should exploit LN function and be combined with “help” signals to optimize CTL efficacy.     

Is there a Rationale for Autologous Breast Reconstruction in Older Patients? A Retrospective Single Center Analysis of Quality of life,Complications and Comorbidities after DIEP or ms‐TRAM Flap Using the BREAST‐Q

Autologous breast reconstruction with the deep inferior epigastric perforator (DIEP) or muscle‐sparing transverse rectus abdominis myocutaneous (ms‐TRAM) flap is a common method in the majority of patients after mastectomy. Because of an increased perioperative risk profile the benefit in older patients is questionable. To assess the postoperative quality of life and peri‐ and post‐operative complications of older compared to younger patients is the aim of this retrospective study. In a retrospective analysis 39 older (i.e. >60 years) and 140 younger patients (i.e. <60 years) with autologous breast reconstruction in the Department of Plastic Surgery at the University Hospital of Erlangen‐Nuernberg were surveyed at least 6 month postoperative using the BREAST‐Q questionnaire. Correlations were generated between comorbidities and complications. Significant differences were observed regarding hospitalization, pre‐existing diseases and the choice of DIEP versus ms‐TRAM flaps. Parameters such as major and minor complications, bulging or hernia and risk factors (e.g. smoking or obesity) showed no significant differences. The results of the questionnaire parameters showed no significant difference between both groups, revealing high satisfaction with the aesthetic result and an improvement in quality of life independent of age. Autologous breast reconstruction after mastectomy generates a gain in quality of life and shows a good to excellent overall satisfaction in older as well as younger patients. Despite a longer hospitalization and a different risk profile there were no significant differences regarding minor and major complications in the postoperative course. Hence autologous breast reconstruction for older patients is justified and should be taken into consideration.     

Emergency arterio‐venous loop for free‐flap defect reconstruction of the lower thigh with a post‐irradiated and heavily infected wound

Although being a safe and standardised procedure, free‐flap reconstruction can be harmful if unpredictable situations occur intraoperatively. The case presented reveals a situation in which an unscheduled interdisciplinary approach allowed to complete our reconstructive aim. An extensive defect at the thigh was planned for reconstruction by means of a free rectus abdominis flap. As the distant part of the flap showed a compromised perfusion during operation and had to be partially discarded, our colleagues from the vascular surgery department created an arterio‐venous loop for anastomosis. This allowed a more distant positioning of the flap and ensured a complete defect reconstruction.     

Effects of Piclamilast,a Selective Phosphodiesterase-4 Inhibitor,on Oxidative Burst of Sputum Cells From Mild Asthmatics and Stable COPD Patients

Oxidative stress associated with increased presence of neutrophils is an important feature of inflammatory airways diseases like asthma or chronic obstructive pulmonary disease. We studied the in vitro effect of piclamilast (RP73401), a selective phosphodiesterase (PDE)-4 inhibitor, compared to theophylline and prednisolone, on respiratory burst of sputum cells from mild asthmatics and COPD patients. Sputum cells were harvested from mild asthmatics and stable COPD patients and treated with piclamilast, theophylline or prednisolone. Respiratory burst was assessed by luminol-dependent chemoluminescence after stimulation with 10 M n-formyl-met-leu-phe (FMLP). Piclamilast inhibited FMLP-induced respiratory burst of sputum cells in a concentration-dependent manner (asthma: EC₅₀ approximately 100 nM, max. inhibition: 97.5±5% at 100 M; COPD: EC₅₀ approximately 1 M, max. inhibition: 70.6±4.5% at 100 M), whereas maximal inhibition observed with theophylline (asthma: max. inhib. 27±15%; COPD: 6±2%, both p < 0.05 vs. piclamilast) and prednisolone (asthma: 16±6%; COPD: 7.8±6.2%, both p < 0.05 vs. piclamilast) was weaker. Inhibition by piclamilast was largely reversed through pretreatment of cells with the adenylcyclase inhibitor SQ22536. We concluded that piclamilast, a selective PDE-4 inhibitor, attenuates the respiratory burst of sputum cells from mild asthmatics and COPD patients in vitro. These data underline the potential of PDE-4 inhibition as a novel therapeutic approach to inflammatory airway diseases like asthma or COPD.     

Strategic use of antimalarial drugs that block falciparum malaria parasite transmission to mosquitoes to achieve local malaria elimination

The ultimate aim of malaria chemotherapy is not only to treat symptomatic infection but also to reduce transmission potential. With the absence of clinically proven vaccines, drug-mediated blocking of malaria transmission gains growing interest in the research agenda for malaria control and elimination. In addition to the limited arsenal of antimalarials available, the situation is further complicated by the fact that most commonly used antimalarials are being extensively resisted by the parasite and do not assist in blocking its transmission to vectors. Most antimalarials do not exhibit gametocytocidal and/ or sporontocidal activity against the sexual stages of Plasmodium falciparum but may even enhance gametocytogenesis and gametocyte transmissibility. Artemisinin derivatives and 8-aminoquinolines are useful transmission-blocking antimalarials whose optimal actions are on different stages of gametocytes. Transmission control interventions that include gametocytocides covering the spectrum of gametocyte development should be used to reduce and, if possible, stop transmission and infectivity of gametocytes to mosquitoes. Potent gametocytocidal drugs could also help deter the spread of antimalarial drug resistance. Novel proof-of-concept compounds with gametocytocidal activity, such as trioxaquines, synthetic endoperoxides, and spiroindolone, should be further tested for possible clinical utility before investigating the possibility of integrating them in transmission-reducing interventions. Strategic use of potent gametocytocides at appropriate timing with artemisinin-based combination therapies should be given attention, at least, in the short run. This review highlights the role that antimalarials could play in blocking gametocyte transmission and infectivity to mosquitoes and, hence, in reducing the potential of falciparum malaria transmissibility and drug resistance spread.     

In vitro and in vivo Biocompatibility of Alginate Dialdehyde/Gelatin Hydrogels with and without Nanoscaled Bioactive Glass for Bone Tissue Engineering Applications

In addition to good mechanical properties needed for three-dimensional tissue engineering, the combination of alginate dialdehyde, gelatin and nano-scaled bioactive glass (45S5) is supposed to combine excellent cellular adhesion, proliferation and differentiation properties, good biocompatibility and predictable degradation rates. The goal of this study was to evaluate thein vitro and in vivo biocompatibility as a first step on the way to its use as a scaffold in bone tissue engineering. In vitro evaluation showed good cell adherence and proliferation of bone marrow derived mesenchymal stem cells seeded on covalently crosslinked alginate dialdehyde-gelatin (ADA-GEL) hydrogel films with and without 0.1% nano-Bioglass^®(nBG). Lactate dehydrogenase (LDH)- and mitochondrial activity significantly increased in both ADA-GEL and ADA-GEL-nBG groups compared to alginate. However, addition of 0.1% nBG seemed to have slight cytotoxic effect compared to ADA-GEL. In vivo implantation did not produce a significant inflammatory reaction, and ongoing degradation could be seen after four weeks. Ongoing vascularization was detected after four weeks. The good biocompatibility encourages future studies using ADA-GEL and nBG for bone tissue engineering application.